From estimates made in 1995, only a small minority of genes in the mammalian genome is thought to be imprinted.98 In humans, more than 25 imprinted genes have been identified, and estimates based on mouse models indicate that as many as 100_200 may exist over the whole genome.98,99 Imprinted genes are involved in many aspects of development including fetal and placental growth, cell proliferation, and adult behavior.99 Several inherited disorders have been attributed to faulty genomic imprinting. Certain aberrations of human pregnancy show that loss of genomic imprinting (LOI) plays an important role in embryogenesis (Table 6.2). For example, ovarian dermoid cysts arise from LOI that result in benign cystic tumors that contain two maternal chromosomes and no paternal chromosome. In contrast, the hydatidiform mole contains a completely andro-genic genome that arises from LOI, so that these tumors contain two paternal chromosomes and no maternal chromosome.
More recently, additional human genetic diseases and cancers listed in Table 6.2 have been ascribed to faulty genomic imprinting. In 1991, the molecular basis of fragile X syndrome, a common form of heritable mental retardation, was associated with a massive expansion of CGG triplet repeats located in the
5'-untranslated region upstream of the FMR1 (fragile X mental retardation) gene.74'100 This syndrome takes its name from the brittle appearance of the X chromosome under a microscope, part of which appears to be dangling by a thread.101 The fragile X site is located at Xq27.3. This was one of the first of about a dozen identified human disorders that are caused by unstable trinucleotide repeat expansions. In normal individuals, FMR1 is a highly conserved gene that contains about 30 (range 7 to ~60) CGG repeats while over 230 repeats occur in most affected persons. In the normal transcript the repeats are unmethylated, but in affected persons they are hypermethylated, which silences the FMR1 gene and causes the absence of the FMR1 protein. Mental retardation is attributed to lack of proper protein expression in neurons during development. Due to X linkage, affected males have more severe phenotypes than affected females, whose phenotype is modulated by the presence of the normal X chromosome.
Several other diseases that are due to faulty imprinting are also listed in Table 6.2. For example, Pal and co-workers observed preferential loss of the maternal alleles on chromosome 11 in 9 of 11 cases of Wilms' tumors where the parental origin of alleles could be followed.102 Similar observations on five additional cases of Wilms' tumors were made by Schroeder et al.103 Scrable and colleagues have found that embryonal rhabdomyosarcomas (malignant pediatric tumors of striated muscle origin) could arise from cells that were clonally isodisomic for paternal loci on chromosome 11.104
Glenn and associates demonstrated that the SNRPN gene, which encodes a small nuclear ribonucleoprotein subunit SmN thought to be involved in splicing of pre-mRNA, is expressed only from the paternally derived chromosome 15q11-q13 in humans with Prader-Willi syndrome.105 More recently, Horsthemke and colleagues performed a molecular analysis at the SNURF-SNRPN locus in 51 patients with Prader-Willi syndrome and 85 patients with Angel-man syndrome that revealed that the majority of these defects were epigenetic mutations. Seven patients with Prader-Willi syndrome (14%) and eight patients with Angelman syndrome (9%) had an imprinting center deletion. Sequence analysis of 32 Prader-Willi syndrome patients and no imprinting center deletion and 66 AS patients and no imprinting center deletion did not reveal any point mutation in imprinting center elements. In patients with Angelman syndrome, they found the imprinting defect occurred on the chromosome that was of maternal grandparental origin, whereas in the patients with Prader-Willi syndrome and no imprinting center deletion, the imprinting defect occurred on the chromosome inherited from the paternal grandmother.106 The fact that epimutations on the maternal chromosome were often present in a mosaic form suggested that in patients with Angelman syndrome and no imprinting center deletion that aberrant DNA methylation responsible for the imprinting defect occurred after fertilization.
Mannens et al. carried out cytogenetic and DNA analyses on patients with Beckwith-Wiedemann syndrome.107 They refined the localization of the syndrome at chromosome 11p15.3-pter to two regions, BWSCR1 and BWSCR2. They found that LOI was involved in the etiology of the Beckwith-Wiedemann syndrome with BWSCR2 since all balanced chromosomal abnormalities ob served at this region were maternally transmitted. Loss of imprinting can cause either biallelic expression (such as IGF2) or silencing (such as CDKN1C) that is found in most sporadic cases of Beckwith-Wiedemann syndrome (Table 6.2).
Another interesting aspect of imprinting is that imprinted genes tend to be clustered in the genome. In humans, the two major clusters are associated with the two major imprinting disorders (Table 6.2). The cluster at chromosome 15q11-13 is linked to the Prader-Willi and Angelman syndromes, and the one at 11p15.5 is linked to the Beckwith-Wiedemann syndrome.
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